To determine if suppression of herpes simplex virus-2 (HSV-2) using a standard dose of acyclovir can reduce the incidence of HIV infection among women in a setting where HSV prevalence is estimated at 80% and where 22% of new HIV infections are attributed to HSV-2.

Study Design

Randomized, double-blinded, placebo-controlled clinical trial.

Setting

Nineteen communities in northwestern Tanzania.

Participants

Women aged 16-35 years who worked in bars, guesthouses, food service, and other recreational facilities and who were infected with HSV-2 as verified by serological test, not pregnant, not breastfeeding, and not infected with HIV.

Intervention

Women were randomly assigned to receive acyclovir, 400 mg twice daily, or placebo. Women were seen every 12 weeks for follow-up and were examined clinically at 6, 12, 24, and 30 months. At each visit participants were interviewed, serum samples were collected, and pills were counted. Pregnancy testing was done for women who reported missed menstrual periods or who thought they might be pregnant. The clinical examination included a genital examination at which time vaginal and cervical specimens were obtained and cervicovaginal lavage performed as well as tests for Trichomonas vaginalis, Chlamydia trachomatis, and Neisseria gonorrhoeae. If ulcers were present, testing for Haemophilis ducreyi, HSV, and syphilis were done.

Treatment adherence was measured using pill counts. In addition, random urine samples were obtained at the 6 and 24 month visits and tested at an independent laboratory for the presence of acyclovir.

Data were analyzed using a modified intention-to-treat (ITT) analysis. The end point was the end of follow-up, date of first positive pregnancy test, the last follow-up visit, or the estimated date of seroconversion, based on the midpoint between last negative and first positive test, which ever was earliest. Secondary ITT analyses included an on-treatment analysis in which patients who stopped taking pills were censored at the time of withdrawal and an on-treatment analysis stratified by estimated adherence within each 12-week period. Adherence was classified as unknown if a participant did not return with unused pills, too few pills, or reported that tablets were lost, stolen, or damaged. For subjects who missed a follow-up visit, adherence was calculated at the previous visit and based upon the number of days since that visit.

Results

Between January 2004 and May 2006, 2719 women screened and 821 enrolled. There were 421 women randomized to placebo and 400 to acyclovir. Only 34 of the 1385 eligible women declined participation; the others were not randomized for other reasons. Eighty-three percent completed follow-up and were included in the primary modified ITT analysis. The characteristics, follow-up time, and reported adherence were similar for both placebo and acyclovir groups.

In the modified ITT analysis, the placebo group had 28 HIV seroconversions (incidence rate of 4.12 per 100 person-years) and the acyclovir group had 27 seroconversions (incidence rate of 4.44 per 100 person-years). The difference in the rates of seroconversion in the groups was not statistically significant. The results from the on-treatment and stratified adherence analyses were similar and supported the absence of effect of acyclovir on reducing HIV seroconversions.

Urine testing of 144 samples from the acyclovir group found that between 33% and 67% had acyclovir present. In the urine samples from the placebo group, 5% had the drug present.

This randomized controlled trial was of high quality. Allocation was random and concealed and study team and participants were blinded to study arm assignments. Follow-up was very good and similar between the two groups. The authors used ITT for the analysis.

In Context

There is substantial evidence of a contributory role of HSV-2 infection to HIV transmission, particularly in sub-Saharan Africa, where an estimated 50% of HIV infections are attributed to HSV-2.(1) Studies have shown a synergistic relationship between HIV and HSV(1,2,3,4) and that HSV acts at the cellular level to increase HIV target cells.(5) As such, it would seem that effective suppression of HSV-2, as has occurred with the acyclovir dose used in this study, might decrease HIV seroconversions in an at-risk population. Other studies using higher doses of acyclovir and similar medications with greater bioavailability have been found to reduce HIV genital(6) and plasma viral loads.(7,8) Although acyclovir 400 mg (twice daily) does suppress HSV, in this population the measurement of adherence is likely to have been overestimated and may have contributed to the study's negative findings. Further studies with higher doses of acyclovir or valacyclovir may be needed to demonstrate a reduction in HIV incidence.

Programmatic Implications

Identifying a medication that can prevent or greatly reduce the risk of HIV infection might have a substantial effect on HIV transmission in sub-Saharan Africa. However, even if there were incontrovertible data for this possibility, inadequate adherence might render such a strategy ineffective from a public health perspective. It is difficult for asymptomatic persons to be highly compliant with medications and even more difficult with twice daily dosing. Furthermore, suppressive therapy is ongoing, further reducing the likelihood of adequate adherence. Although efforts to identify effective prevention strategies, including methods to enhance adherence and demonstrate the effectiveness of suppressive HSV therapy to reduce HIV incidence, public health programs should continue to focus on known effective HIV prevention strategies.